Update on TB-IRIS
Graeme MeintjesUniversity of Cape Town
Imperial College London
SA HIV Clinicians Society Conference, Cape Town, 27 Nov 2012
Paradoxical TB-IRIS
Patient diagnosed with TB and started on TB treatment
Typically improving on TB treatment then start ART
8-43% of patients on TB treatment when starting
ART develop paradoxical TB-IRIS
Recurrence of TB symptoms and new or recurrent clinical manifestations of TB
(Usually 1-3 weeks after starting ART)
OUTLINE
• Neurological TB-IRIS
• Prolonged TB-IRIS
• Important differential diagnoses
• Corticosteroids• Corticosteroids
• Pathogenesis
• Risk factors and ART timing
IRIS meta-analysisPooled cumulative incidences as % (95% credibility intervals)
Incidence (%) Mortality (%)
CMV retinitis 37.7 (26.6 - 49.4) -CMV retinitis 37.7 (26.6 - 49.4) -
Cryptococcal meningitis
19.5 (6.7 - 44.8) 20.8 (5.0 - 52.7)
Tuberculosis 15.7 (9.7 - 24.5) 3.2 (0.7 - 9.2)
PML 16.7 (2.3 - 50.7) -
Muller, Lancet Infect Dis 2010;10:251
Neurological TB-IRIS
• 12% with paradoxical TB-IRIS have CNS involvement
• Up to 47% of TBM patients starting ART develop IRIS
• Features– Meningitis– Meningitis
– Tuberculoma/s
– Radiculomyelopathy
• Occurs in patients with or without CNS TB prior to ART
• Outcomes– 12% mortality and 18% loss to follow-up in one series
– 25% mortality in another series
– Neurological disabilityPepper et al, Clin Infect Dis 2009Marais et al, Clin Infect Dis 2012
TBM diagnosis TBM-IRIS
Slide courtesy Suzaan Marais
TBM-IRIS with expressive aphasia
Slide courtesy Suzaan Marais
TBM and PTB prior to ART
TB-IRIS with enlarging mass lesion/cerebral oedema
Patient died
CSF Neutrophils and TBM-IRIS
6060
650
Non
IRIS
Cells
/mm
3
IRIS
p=0.01 p<0.0001
0
20
40
TBM diagnosis
Day 0
ART Start
Day 142 weeks post ART/IRIS
Day 28
Cells
/mm
MaraisCID 2012
Prolonged TB-IRIS
• Typically suppurativelymphadenitis & abscesses
• Systemically well
• Tuberculomas & cerebral abscessesabscesses
• TB-IRIS duration (n = 176)
– Median: 70 days
– IQR: 41-111 days
– IRIS > 90 days: 36%
Bana, unpublished
Prolonged TB-IRIS: management
• Often repeated aspirations required
• Avoid surgical drainage
• Repeat TB culture (and DST if positive)
• Role of corticosteroids for more than 4 • Role of corticosteroids for more than 4 months questionable unless CNS involved
• Experimental therapies – Thalidomide and TNFa-blockers
• Consider prolonging TB treatment– How adequate is drug penetration?
Key points in TB-IRIS diagnosis
1. Diagnosis of TB confirmed or very likely?
2. Improvement on TB treatment prior to ART?
3. Symptom onset typically 1-3 weeks on ART
4. Deterioration with inflammatory features of TB
5. Consider and exclude differential diagnoses
6. Exclude drug-resistant TB
No confirmatory diagnostic test
100 TB-IRIS suspects
screened using
case definitionKEY FINDING
Undiagnosed
rifampicin resistance in
10.1% of patients
(95% CI 3.9-16.4%)
presenting with TB-presenting with TB-
IRIS, after exclusion of
known rifampicin
resistance and
alternative
opportunistic diseases
Lymph node enlargement
Differential diagnoses
• Lymphoma
• Kaposi’s
• Castleman’s disease• Castleman’s disease
Consider malignancy particularly
when LN remains firm
• NTM IRIS
• Cryptococcal IRIS
Hepatic TB-IRIS case
• 4 months treatment for drug-sensitive pericardial TB
• Clinically improved, then started ART
• 3 weeks later presented with fever and hepatomegaly
• LFT: Bil 52, CBil 31, Alk Phos 1081, GGT 1468, ALT 82, AST 88
• CD4 rise from 64 to 221
• Biopsy AFB- and TB culture -
Case courtesy of Mark Sonderup
Hepatic TB-IRIS vs DILI
Hepatic TB-IRIS
• RUQ pain, nausea and vomiting
• Tender hepatomegaly
• Cholestatic LFT derangement
Drug-induced liver injury
• Similar symptoms
• Typically not hepatomegaly
• Transaminitis +/- jaundice• Cholestatic LFT derangement
• +/- mild jaundice
• Usually other TB-IRIS
manifestations
• Absence of other TB-IRIS features
Patients may present with clinical picture between these two
- Biopsy or treat as DILI
Two conditions may co-exist
Other important differential diagnoses
Manifestation Differential diagnoses
Pulmonary infiltrate Bacterial pneumonia
PCP
Kaposi’s sarcoma
Pleural effusion Bacterial empyema
Kaposi’s sarcoma
Meningitis Bacterial
Cryptococcal
Space-occupying lesion Toxoplasmosis
Cryptococcoma
Primary CNS lymphoma
Fever with general deterioration Bacterial sepsis
NTM
Kaposi’s or lymphoma
*Consider and investigate for DR-TB in all scenarios
Randomised controlled trial of prednisone vs placebo
GF Jooste Hospital, Cape Town, 2005-8
• 110 participants
• Life-threatening TB-IRIS was an exclusion
• Prednisone (or placebo) dose • Prednisone (or placebo) dose
– 1.5 mg/kg/d for 2 weeks then
– 0.75 mg/kg/d for 2 weeks
• Open-label prednisone at physician discretion if clinical deterioration/relapse
Meintjes, AIDS 2010
Primary endpointCumulative number of days hospitalized and outpatient
therapeutic procedures (counted as 1 additional day), ITT analysis
Placebo
arm
Prednisone
arm
P-value
arm
N = 55
arm
N = 55
Total days hospitalized 463 282 -
Total number outpatient procedures 28 24 -
Cumulative primary endpoint (median, IQR) 3 (0-9) 0 (0-3) 0.04
Secondary endpoints
• Consistent benefit, maximal in first 4 weeks, across a range of secondary outcome measures
– Symptom score
– Karnofsky performance score
– MOS-HIV questionnaire (quality of life assessment)
– Chest radiology score
– C-reactive protein
• 10/55 in prednisone arm relapsed after completing study drug and required re-initiation of prednisone
– 4 weeks appeared to be too short for these patients
Adverse events
Placebo
arm
Prednisone
arm
P-value
Death on study 2 (4%) 3 (5%) 0.65
Corticosteroid side effects
while on study drug*
3 (5%) 8 (15%) 0.11
while on study drug*
Infections while on study
drug
17 (31%) 27 (49%) 0.05
Severe infections** 4 (7%) 2 (4%) 0.40
* Included BP > 140/90, oedema, hyperglycaemia, hypomania, acne, Cushingoid features, gastritis symptoms
** WHO stage 4 or invasive bacterial infection
Corticosteroids
for paradoxical TB-IRIS?
Symptom improvementReduced hospitalisation? Survival benefit in life threatening cases
Potential adverse effects- Kaposi’s- Infections- Metabolicthreatening cases - Metabolic
Diagnostic uncertainty
CASE: 49 year old HIV+ man with CD4=29, diagnosed with drug-
susceptible PTB. Started ART 2 weeks after TB treatment. 2 weeks later
developed recurrent TB symptoms, worsening of pulmonary infiltrate and
new pleural effusion.
MANAGEMENT: Antibiotic, aspiration of pleural effusion, prednisone. TB
cultures of sputum and effusion were negative at TB-IRIS.
Pathogenesis of paradoxical IRIS
Recovery of pathogen-specific
immune responses and T-cell
activation
Recovery of innate immune
function
Inflammatory reactions
directed to antigens of
opportunistic infection
Pro-inflammatory
cytokines and
chemokines
Defective immune
regulatory function
Tadokera, Eur Resp J 2011;37:1248
22 TB-IRIS vs 22 controlsControls were HIV-TB patients
sampled at 2 weeks on ART
Hypercytokinaemia accompanies HIV-tuberculosis
immune reconstitution inflammatory syndromeIL-6
IRIS Non-IRIS
IRIS IRISNon-IRIS Non-IRIS
IFN-γ TNF-α
0.003
Major TB-IRIS risk factors
• Low CD4 count
• Short interval between TB treatment and ARTART
• Disseminated TB
Risk of
IRIS
Risk of HIV
disease progression
MORTALITY MORTALITY
Earlier
ART
Deferred
ART
MORTALITY MORTALITY
When to start ART after recent diagnosis of OI?
Several recent clinical trials
SAPiT IRIS incidence(IRIS cases/100 person years)
ART timing and primary endpoints
Death/AIDS
p = 0.45 Death/AIDS
Death
p=0.006
38% �
p = 0.45 Death/AIDS
p = 0.73
ART timing and primary endpoints in patients with CD4 < 50
Death
p=0.006
38% �
Death/AIDS
p=0.02
42% �
Death/AIDS
p=0.06
68% �
* CAMELIA data represents all patients in trial, majority had CD4 < 50 (median CD4 =25)
Implications
• In patients with CD4 < 50 : start ART at 2 weeks
– Even though more likely to develop IRIS with early ART
– Benefit most from early ART in terms of survival and preventing AIDS events
• In patients with CD4 > 50
– ART can be deferred ~ 8 weeks to reduce risk of IRIS
– Except patients with severe clinical disease, organ system dysfunction, low performance score, low BMI or Hb as these are associated with higher mortality
Acknowledgements• Robert Wilkinson• Gary Maartens• Katalin Wilkinson• Suzaan Marais• Charlotte Schutz• Tasnim Bana• Maia Lesosky• Molebogeng Rangaka• Chelsea Morroni• Tolu Oni• Tolu Oni• Dominique Pepper• Kevin Rebe• Rene Goliath• Helen van der Plas• Marc Mendelson• Priscilla Mouton• Bob Colebunders• Anali Conesa Botella• Raylene Titus• Keira Skolimowska• Kerryn Matthews• Rebecca Tadokera